Pharmacokinetics/pharmacodynamics of marbofloxacin in a Pasteurella multocida serious murine lung infection model

摘要

Marbofloxacin is a third-generation fluoroquinolone developed solely for veterinary medicine with a broad spectrum of antibacterial activity against some Gram-positive and most Gram-negative bacteria, including the bovine respiratory tract pathogen, Pasteurella multocida. The objective of our study was to elucidate the pharmacokinetics and pharmacodynamics of marbofloxacin in a Pasteurella multocida infected murine lung model, and to estimate the magnitudes of pharmacokinetics-pharmacodynamics parameters associated with various effects. The pharmacokinetic studies revealed marbofloxacin kinetics in infected mice were linear over a dose ranging from 1.25 to 10?mg/kg of body weight. The protein binding in the plasma of neutropenic infected mice was 29.77?%. The magnitudes of the ratio of the free-drug area under the concentration-time curve over 24?h to MIC (fAUC0-24h/MIC) associated with static effect, a 2 log10 reduction and a 3 log10 reduction of bacterial counts were 40.84, 139.34, and 278.08?h, respectively. Based on the dose range study, marbofloxacin exhibited concentration-dependent killing and the fAUC/MIC was the PK/PD index that correlated best with efficacy (R2?=?83?%). On the basis of a bactericidal effect goal of fAUC0-24h/MIC of 278.08?h, if marbofloxacin is used for the treatment of P. multocida serious lung infection with an MIC90 of 0.12?μg/ml, the current dose (2?mg/kg) would fail to achieve a bactericidal effect. It would benefit from higher doses (4?~?6?mg/kg) than those commonly used in clinical practice.